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Here, we report a de novo synthesized amphiphilic zwitterionic copolymer that co\u2010assembles with phospholipids into protein\u2010free nanodiscs (zNDs, \u223c15.5\u00a0nm). Liposome co\u2010flotation and F\u00f6rster resonance energy transfer (FRET) assays reveal a three\u2010stage morphogenetic process: polymer insertion, membrane disruption, and liposome\u2010to\u2010nanodisc reassembly through membrane remodeling. The resulting zNDs exhibit high colloidal stability under physiological conditions and efficiently cross the BBB via choline transporter\u2010mediated transcytosis. In orthotopic glioblastoma models, zNDs penetrate tumors deeply, enter cells through clathrin\u2010mediated endocytosis, and escape endo\u2010lysosomal compartments. Incorporation of lipid\u2013drug conjugates allows delivery of honokiol, which disassembles 3D tumor spheroids, suppresses tumor growth in orthotopic models, and extends median survival by nearly 2.5\u2010fold without systemic toxicity. This study establishes a modular, protein\u2010free nanodisc platform that integrates rational polymer design with active BBB transport, offering a versatile strategy for deep therapeutic delivery in central nervous system malignancies and providing mechanistic principles that guide future optimization of BBB\u2010penetrant nanocarriers.<\/jats:p>","DOI":"10.1002\/anie.2167334","type":"journal-article","created":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T17:33:36Z","timestamp":1775928816000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Amphiphilic Zwitterionic Polymers Induce Liposome Morphogenesis into Nanodiscs for Deep Glioblastoma Infiltration"],"prefix":"10.1002","volume":"65","author":[{"given":"Yeying","family":"Li","sequence":"first","affiliation":[{"name":"College of Pharmacy Anhui University of Chinese Medicine  Hefei China"},{"name":"Shandong Laboratory of Yantai Drug Discovery Bohai Rim Drug 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